Interpretive Summary: The incidence of obesity has risen over the last three decades in the United States and worldwide, and has become a major public health concern because obesity often leads to heart disease, high blood pressure, and diabetes. Abnormalities in fat and carbohydrate metabolism are likely to contribute to the development of diseases associated with obesity. Furthermore, the intakes of certain nutrients may influence the metabolic abnormalities that contribute to obesity associated diseases. For instance, the increase in obesity has been paralleled by an increase in fructose consumption. It has also been recognized that typical Western diets can lead to marginal intakes of copper. The results of the present study indicate that the combination of fructose intake and marginal copper deficiency interact in a manner that potentiates the development of nonalchoholic fatty liver disease in laboratory rats. Dietary fructose decreased the absorption of copper. Because copper intake was marginal, the decrease in copper absorption caused by dietary fructose caused a severe drop in liver copper content that led to impaired fat metabolism and high iron content in the liver. The resulting combination of impaired fat metabolism and high liver iron concentration caused accumulation of fat in the liver and liver damage. Thus, marginal copper intake, which is not uncommon, may contribute to the development of fatty liver disease when dietary carbohydrate intake contains a high percentage of fructose, which is common in typical modern diets.